REACTION OF THE CARCINOGEN DIMETHYLNITROSAMINE WITH NUCLEIC ACIDS IN VIVO

127

Summary.-The reaction of the hepatocarcinogen N,N-dimethylnitrosamine has been compared with that of methyl methanesulphonate, a methylating agent which is not a liver carcinogen. Consistent differences have been observed in the reaction of rat liver DNA in vivo with these agents; 06-alkylation and the production of unidentified acid-labile products were distinctive features of the reaction with the carcinogenic nitroso compound but were undetectable or in low yield, respectively, after reaction with the alkyl sulphonate. Evidence has been obtained for the excision of these reaction products in animals treated with the hepatocarcinogen and the significance of their relative stabilities is discussed.

Section: Methylation Of Dna In Vivosupporting

confidence: 87%

“…RNA studies described previously have demonstrated radioactive labelling of the -j purine bases via the 1-carbon pool (Craddock and Magee, 1963;Whittle, 1969;McElhone et al, 1971). In the present work metabolic labelling of DNA (expressed as dpm/,umol of purine bases) was 5-6 times less ( Fig.…”

Section: Mletabolic Labelling Of Dnasupporting

confidence: 54%

Comparative Studies of the Hepatocarcinogen N,N-Dimethylnitrosamine in vivo: Reaction Sites in Rat Liver DNA and the Significance of their Relative Stabilities

O’Connor¹,

Capps²,

Craig³

1973

127

“…1) (Magee and Hultin, 1962;Magee and Farber, 1962;Craddock and Magee, 1963). This compound was shown to alkylate nucleic acids and proteins of various organs in rat and mouse in vivo to different degrees and there was some correlation between the degree of methylation of the nucleic acids and the sites at which tumours were induced (Lee et al, 1964).…”

mentioning

confidence: 99%

The induction of tumours in the rat by a single oral dose of N-nitrosomethylurea.

Leaver¹,

Swann²,

Magee³

1969

“…The presently observed decrease of reactivity toward the -SH reactor, p-CMB, following chronic DEN administration, suggests two alternatives: (a) that during in vivo degranulation the -SH groups which arise undergo intramembrane recombination, or combination with reactive metabolic inltermediates of the carcinogens (cf. Craddock, 1964) or (b) that, with the progression of the neoplastic change, the mechanism governing the osmotic behaviour of the ER membrane becomes increasinglysegregated from the sites of sulphydryl-disulphide interchange activity. …”

Section: Mixed-function-oxidase Activitiesmentioning

confidence: 99%

Ultrastructural and Metabolic Determinants of Resistance to Azo-dye and Susceptibility to Nitrosamine Carcinogenesis of the Guinea-pig

Bryant¹,

Sohal²,

Argus³

et al. 1977

Summary.-During diethylnitrosamine (DEN) administration, a distinctive difference was observed between rats and guinea-pigs in the sequence of ultrastructural changes in the hepatic endoplasmic reticulum (ER). In DEN-induced hepatic tumour cells in the guinea-pig there was extensive proliferation of the rough ER, while the smooth ER was quite sparse; in the premalignant liver the opposite was noted. This is in contrast to the rat, in which administration of either DEN or 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) brings about, in both premalignant and malignant hepatic tissue, proliferation of the smooth ER and sparsity of the rough ER. Yet, as in the rat, the number of ribosomes on the outer surface of the guinea-pig liver rough ER is greatly reduced and this is paralleled by a 49% decrease of the RNA/protein ratio as early as 4 weeks of nitrosamine administration. The decrease of RNA/protein ratio and ultrastructurally observed loss of ribosomes from the ER, following nitrosamine administration, correlate with a decrease of photometric response of microsomal suspensions to the sulphydryl probe, p-chloromercuribenzoate. While azo-dye-reductase activity is higher in untreated rats than in untreated guinea-pigs, feeding 3'-Me-DAB for 6 weeks brings about a 76% decrease in the rat, but no significant decrease in the guinea-pig, which is refractory to azo-dye carcinogenesis. Thus, the ability of the liver to inactivate the dye is greatly decreased in the rat, but not in the guinea-pig, as administration progresses toward the threshold dose for tumorigenesis. On the other hand, constitutive levels of nitrosamine dealkylase are identical in the 2 species and remain essentially unchanged following administration of DEN for 10 weeks. Inasmuch as nitrosamine dealkylation represents activating metabolism, this provides a rationale for the comparable susceptibility of the rat and guinea-pig to DEN carcinogenesis. Of the 2 enzymes in the 2 species, it is only azo-dye reductase in the guinea-pig which appears to be unregulated by glucose repression, since starvation brings about no change in this activity. Starvation-induced increase of azo-dye reductase in the rat is not influenced by administration of 3'-Me-DAB and only slightly by DEN. The starvation-induced increase of nitrosamine dealkylation is abolished, however, in both species by administration of DEN but only slightly decreased by 3'-Me-DAB.GUINEA-PIGS have long been known to (3'-Me-DAB) remains unimpaired even be totally resistant to the hepatocarcino-when administration of the dye at 0.12% genic action of aminoazo dyes and aro-dietary level is combined with partial matic amines. The resistance of the hepatectomy, a powerful cocarcinogenic guinea-pig tothe potent hepatic carcinogen, stimulus (Gosch, Arcos and Argus, 1970).